Proper medical treatment of pain remains a challenge for patients and healthcare professionals. Optimal pharmacologic management of pain requires selection of analgesic drugs that achieve rapid efficacy with minimal side effects. Traditionally, opioid analgesics have provided the most important options for pain treatment. However, misuse and abuse of opioids is a widespread social and medical problem and may deter physicians from prescribing these useful drugs.
In addition, accidental and intentional overdose with prescription and/or over-the-counter (OTC) drugs is a serious health problem that is associated with thousands of fatalities every year. Opioid overdose is a significant and growing problem associated with drug abuse, but overdoses also occur accidentally (for example when a child obtains and ingests an opioid), or intentionally (e.g., when related to suicide attempts). Accidental overdose can also commonly occur when unusually potent batches of illicit opioids are ingested by drug addicts or other abusers
Opioid abuse is an increasing problem, and oxycodone has become one of the most widely abused drugs. The drug is known as “a poor man's heroin” because of its comparatively lower street price. Moreover, crushing and snorting intranasally the delayed release form of oxycodone (known by the brand name as Oxycontin®), results in rapid drug release and absorption, which results in high peak blood concentrations that produce a quick “high” but can also precipitate a fatal overdose (Aquina et al (2009) Post Graduate Medicine 121: 163-167). Necrosis of intranasal structures, similar to the damage associated with cocaine use, is also a consequence prolonged Oxycontin® abuse by snorting crushed tablets.
A further shortcoming of many opioids is their generally low oral bioavailability. The poor oral bioavailability results in variable blood levels, and consequently variable patient response—a highly undesirable feature in the treatment of pain where rapid and reliable relief is critical.
Researchers and the pharmaceutical industry have sought to prevent the potential harmful effects of opioid overdose by creation of various drug formulations. For example, opioids have been combined with opioid antagonists. Such formulations are designed to counteract an oral opioid if the formulation is disrupted (e.g., crushed) prior to oral administration, or if the drug is taken administered parenterally (e.g., injected intravenously). To cite an example of a non-opioid drug with known abuse potential, extended release methylphenidate (Concerta®) has been formulated in a paste that can preclude administration by snorting or injection. Other compositions have been coated with emetic agents in quantities that—if administered in moderation as intended—no emesis occurs; however, if excessive amounts are ingested, emesis is induced to prevent overdose. However, such methods, as well as conventional controlled-release formulations, are often ineffective and can be circumvented.
In addition to Oxycontin®, oxycodone is also an ingredient of well-known drugs such as Percodan®, Percocet®, Roxicet®, and Tylox®. As a semi-synthetic narcotic derived from thebaine, oxycodone is also available in oral formulations combined with aspirin, phenacetin, and caffeine. A typical adult dose of oxycodone is 2.5-5 mg administered orally as the hydrochloride or terephthalate salt every 6 hours. While typically used for the relief of moderate to moderately severe pain, oxycodone can also produce drug dependence of the morphine type. Therapeutic plasma concentrations for analgesia typically range from 10-100 ng/mL, and the toxic plasma concentration is greater than 200 ng/mL.
Various types of prodrugs have been proposed to improve the oral bioavailability of opioids. These have included simple ester conjugates that are subject to hydrolysis by plasma esterases.
Moreover, the rapidity of ester hydrolysis within the gut or through first-pass metabolism in the liver has further limited the utility of this approach. More sophisticated ester-conjugated opioid prodrugs have been synthesized. However, in the 20 years since ester conjugates were first reported, no such prodrugs have been approved as marketed products, which suggests that this approach has not been successful.
Consequently, improved methods are urgently needed to make pharmaceutically effective oxycodone compounds, along with compositions and methods of using such compounds, to reduce the potential for overdose and to reduce or deter opioid substance abuse while maintaining their intended analgesic utility. Potentially useful compounds may also prevent—or substantially diminish or delay—uptake into the brain if the compounds were administered by routes other than approved oral administration.
Ideally, a prodrug moiety and its linkage to a particular opioid would be cleaved at an appropriate rate and site, which would then release the active opioid compound into the blood and provide the intended analgesic benefit. There remains a critical need for the treatment of severe pain with opioids using products that retain all their pharmacological advantages but sharply reduce their principal limitations, including adverse gastrointestinal effects (e.g., constipation), variable bio availability after oral dosing, non-opioid overdose, and misuse, illegal/illicit use, and product tampering.